Volume 34, No 10, Oct 2024

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 34 Issue 10, October 2024: 707-724   |  Open Access

ORIGINAL ARTICLES

Structural basis for linker histone H5–nucleosome binding and chromatin fiber compaction

Wenyan Li^1,2,† , Jie Hu^1,2,† , Feng Song^3,4,† , Juan Yu^1,† , Xin Peng^1,2 , Shuming Zhang⁵ , Lin Wang^1,2 , Mingli Hu^1,2 , Jia-Cheng Liu⁶ , Yu Wei^1,2 , Xue Xiao^1,7 , Yan Li¹ , Dongyu Li^1,2 , Hui Wang^1,2 , Bing-Rui Zhou⁸ , Linchang Dai^1,2 , Zongjun Mou^1,2 , Min Zhou¹ , Haonan Zhang^1,2 , Zheng Zhou^1,2 , Huidong Zhang⁹ , Yawen Bai⁸ , Jin-Qiu Zhou⁶ , Wei Li^1,7 , Guohong Li^1,2,3,* , Ping Zhu^1,2,*

¹Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
²University of Chinese Academy of Sciences, Beijing, China
³New Cornerstone Science Laboratory, Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China
⁴Shandong Key Laboratory of Biophysics, Institute of Biophysics, Dezhou University, Dezhou, Shangdong, China
⁵Department of Public Health Laboratory Sciences, West China School of Public Health, Sichuan University, Chengdu, Sichuan, China
⁶The State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
⁷National Laboratory for Condensed Matter Physics and Key Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China
⁸Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
⁹Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
^†These authors contributed equally: Wenyan Li, Jie Hu, Feng Song, Juan Yu
Correspondence: Guohong Li(liguohong@whu.edu.cn)Ping Zhu(zhup@ibp.ac.cn)

The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.

https://doi.org/10.1038/s41422-024-01009-z

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